Pain is one of the primary indications for medical marijuana and novel cannabinoid (CB) drugs are under development as candidate analgesics. However, empirical support for CBs as analgesics has been inconsistent. The antinociceptive efficacy of 9-tetrahydrocannabinol (THC), the primary active constituent of marijuana, and other CBs has been demonstrated in many preclinical assays of acute and chronic inflammatory pain. Contrastingly, the analgesic effects of CBs in humans have been unreliable. This discrepancy between preclinical and clinical results may be associated with an overreliance of preclinical research on assays that measure PAIN-STIMULATED BEHAVIOR, defined as behavior that is increased in rate and/or intensity following delivery of a noxious stimulus. Antinociception in these assays is indicated by a decrease in pain-stimulated behaviors, which can be produced by either a decrease in sensory sensitivity to a noxious stimulus (i.e. true analgesia) or by false positive motor impairment. This application proposes that preclinical assays of pain-stimulated behavior are vulnerable to false-positive effects associated with CB- induced motor impairment and thereby overestimate CB analgesic efficacy. We propose to address this weakness by assessing the effects of CBs in a novel assay of PAIN-DEPRESSED BEHAVIOR. Assays of pain-depressed behavior assess behavior that is decreased in rate and/or intensity following delivery of a noxious stimulus, and antinociception in these assays is indicated by increases in behavior. This feature renders assays of pain-depressed behavior insensitive to false positive motor impairment. Additionally, assays of pain-depressed behavior model clinically relevant pain-related functional impairment and depressed mood. In one example, lever pressing for intracranial self-stimulation (ICSS) is depressed following delivery of an intraperitoneal injection of lactic acid and this pain-induced depression of ICSS is blocked by classic analgesics. Importantly, pain-induced depression of ICSS is not blocked by kappa opioid agonists and dopamine antagonists, drugs that produce false positive antinociception in assays of pain-stimulated behavior but are ineffective to treat pain in humans. Because no studies have evaluated the effects of CBs in assays of pain- depressed behavior, this application proposes to assess the effects of a variety of CB receptor-selective and -nonselective compounds in complementary assays of pain-stimulated and pain-depressed behavior. [I hypothesize that CB-induced antinociception under conditions of acute inflammatory pain is mediated by false- positive motor-impairment. Contrastingly, during chronic inflammation in which CB receptors are upregulated in the immune system, I hypothesize that CBs will produce true antinociception.] The primary goal of this project is to assess antinociceptive effects of CBs using a model that may be more predictive of analgesia in humans.